4-substituted coumarins

ABSTRACT

4-SUBSTITUTED COUMARINS HAVING THE FOLLOWING STRUCTURAL FORMULA ARE DISCLOSED:   2-(O=),4-R1,5,6-((-Z-O)(-R2)(-R3))-2H-PYRAN   WHEREIN R1 IS (METHYLSULFINYL)METHYL, (METHYLSULFONYL) METHYL, ACETYL(METHYLTHIO)METHYL, DIMETHOXYMETHYL, FORMYL, HYDROXYMETHYL, (ARYLIMINO)METHYL, (ARYLAMINO) METHYL OR (OXIMINO)METHYL; Z IS AN AROMATIC OR HETEROAROMATIC NUCLEUS; R2 AND R3 ARE HYDROGEN, HALOGEN, ALKYL, ARALKYL, ARYL, ALKOXY, ACYLAMINO, OR HYDROXY. THESE COMPOUNDS ARE PREPARED BY THE FOLLOWING REACTION SCHEME:   (=CH(-OH)-Z-)(-R3)(-R4)&gt;C-CO-CH2-SO-CH3   --PH3P=CHCO2R4---&gt;   2-(O=),4-(CH3-SO-CH2-),5,6-((-Z-)(-R2)(-R3))-2H-PYRAN   WHEREIN R4 IS LOWER ALKYL. THE 4 - ((METHYLSULFINYL)METHYL)COUMARINS ARE THEN CONVERTED TO OTHER 4-SUBSTITUTED COUMARINS OF THIS INVENTION. THE COMPOUNDS OF THIS INVENTION ARE USEFUL AS GASTRIC ANTISCRETORY AGENTS ARE INDICATED IN CONDITIONS SUCH AS GASTRIC HYPERACIDITY.

United States Patent 015cc 3,784,600 4-SUBSTITUTED COUMARINS Max vonStrandtmann, Rockaway Township, David T. Connor, Parsippany, and JohnShavel, Jr., Mendham, N.J., assignors to Warmer-Lambert Company,MOl'l'lS Plains, NJ. No Drawing. Filed Oct. 22, 1971, Ser. No. 191,830Int. Cl. C0711 7/24 U.S. Cl. 260-343.2 R 18 Claims ABSTRACT OF THEDISCLOSURE 4-substituted coumarins having the following structuralformula are disclosed:

l a 1 21/ o R (I) wherein R is (methylsulfinyl)methyl, (methylsulfonyl)methyl, acetyl(methylthio)methyl, dimethoxymethyl, formyl,hydroxymethyl, (arylimino)methyl, (arylamino) methyl or (oximino)methyl;Z is an aromatic or heteroaromatic nucleus; R and R are hydrogen,halogen, alkyl, aralkyl, aryl, alkoxy, acylamino, or hydroxy.

These compounds are prepared by the following reaction scheme:

0 R2 Ilia Cm crr, I iL-CHBECH Ph P=CHCOzR4 W wherein R is lower alkyl.

The 4 [(methylsulfinyl)methyl]coumarins are then converted to other4-substituted coumarins of this invention.

The compounds of this invention are useful as gastric antiscretoryagents and are indicated in conditions such as gastric hyperacidity.

The present invention is concerned with 4-substituted coumarins havingthe following structural formula:

LTJ =0 wherein R is (methylsulfinyl)methyl, (methylsulfonyl) methyl,acetyl(methylthio)methyl, dimethoxymethyl, formyl, hydroxymethyl,(arylimino)methyl, (arylamino) methyl or (oximino)methyl; Z is anaromatic or heteroaromatic nucleus, such as benzene, naphthalene,phenanthrene, anthracene, pyridine, quinoline, isoquinoline, carboline,thiophene and furane; R and R are hydrogen, halogen, alkyl, aralkyl,aryl, alkoxy, acylamino, or hydroxy.

In the definitions for R R and R the term aryl denotes a monocyclichydrocarbon radical preferably of 6 to carbon atoms, for example,phenyl, tolyl, and the like. The term alkyl denotes a lower aliphatichydrocarbon radical having 1 to 7 carbon atoms in the carbon chain; forexample, methyl, propyl, isopropyl and the like. The term aralkylencompasses alkyl groups in which an aryl group as defined above issubstituted for a hydrogen atom such as benzyl, phenethyl, and the like.The term acyl denotes those radicals derived from carboxylic acids ofless than 12 carbon atoms, preferably the lower alkanoic acid; forexample, acetic, propionic, butyric and the like. Also, preferred arethe monocyclic carboxylic acids such as benzoic and toluic acids.

The compounds of this invention exhibit antisecretory properties inseveral species of hosts. For example, when they are tested inaccordance with the procedure described by Shay et al., Gastroentrology5, 43, (1945) and Winter et al., Proc. Soc. Exper. Biol. Med. 111, 544(1960). These compounds exhibit the desired antisecretory eifect at adose of 50 to mg./kg.

In order to use these compounds, they are formulated with diluents suchas lactose into dosage forms such as tablets or capsules, or they can becombined with diluents such as water for injection and formulated intodosage forms suitabe for injection.

The compounds of this invention are indicated to pro vide symptomaticrelief in conditions such as gastric hyperacidity. The general dosagerange is about 50-100 mg. two or three times daily, orally or byinjection.

According to the present invention, compounds of Type I above wherein Ris -CH SOCH are prepared from the corresponding fl-ketosulfoxides ofType II by the following reaction scheme:

ed to 4-formylcournarins by the reaction sequence shown below:

0 R1 CH g CH3 CH5: C O

CHaC6 l Ig/CHaOH aqueous hydrochloric acid R: (EEO Z N4-formylcournarins are key intermediates for the synthesis of many novelcoumarins. Examples are shown below:

IT; COgH IT: CHzOH Z l .O =0 I I R; RI

\A O N RE I g: a 4 l a CHO w Ra \HONHz-HCI R1 CH=NOH Arylamines 0 I 0 rRa R: CH=N--Ar 0 I) o R:

NBBH

R1 CHzNH-Ar In order to illustrate the practice of this invention thefollowing examples are included.

phosphorane (17.4 g., 0.05 m.) was added and refluxing was continued fora further 16 hours. The reaction mixture was cooled, the product wasfiltered otf and recrys- 4 tallized from ethanol to give white crystals(9.4 g., 84% M.P. 203-204".

Analysis.Calcd. for C H O S (percent): C, 59.44; H, 4.54; S, 14.42.Found (percent): C, 59.67; H, 4.54; S, 14.41.

EXAMPLE 2 3-hydroxy-p-[ (methylsulfiny1)methyl] -2-pyridineacrylic acidd-lactone Prepared by the general procedure described above.Recrystallization from methanol gave yellow crystals, M.P. 176177 (77%yield).

Analysis.-Calcd. for C H N0 S (percent): C, 53.89; H, 4.06; N, 6.27; S,14.36. Found (percent): C, 53.94; H, 4.11; N, 6.38; S, 14.52.

EXAMPLE 3 7-fluoro-4-hydroxy-p- (methylsulfinyl)methyl]-3-quinoline-acrylic acid o-lactone Prepared by the general methoddescribed above. Product was isolated in 12% yield. Recrystallizationfrom DMF gave yellow crystals, M.P. 223-224.

Analysis.-Calcd. for C H FNO S (percent): C, 57.73; H, 3.46; N, 4.81; S,11.01. Found (percent): C, 57.74; H, 3.47; N, 4.77; S, 10.98.

EXAMPLE 4 3-hydroxy-13-[ (methylsulfinyl) methyl] -2-naphthaleneacrylicacid o-lactone Prepared by the general procedure described above.Recrystallization fi-om DMF gave pale-yellow crystals (93% yield). M.P.248249.

Analysis.-Calcd. for C H O S (percent): C, 66.16; H, 4.44; S, 11.77.Found (percent): C, 66.37; H, 4.45; S, 11.73.

EXAMPLE 5 l-hydroxy-p-[ (methylsulfinyl) methyl]-2-naphthaleneacrylicacid fi-lactone Prepared by the general method described above.Recrystallization from DMF gave pale-yellow crystals yield). M.P.215-216.

Analysis.-Calcd. for C H O S (percent): C, 66.16; H, 4.44; S, 11.77.Found (percent): C, 66.11; H, 4.49; S, 11.63.

EXAMPLE 6 2-hydroxy-/3-[ (methylsulfonyl)methyl]-1-naphthaleneacrylicacid o-lactone Prepared from 1-[(methylsulfonyl) acetyl]-2-naphthol (10g.) by the general procedure as described in Example 1.Recrystallization gave yellow crystals (7.54 g., 69%), M.P. 259-262.

Analysis.Calcd. for C H O S (percent): C, 62.49; H, 4.20; S, 11.12.Found (percent): C, 62.19; H, 4.28; S,

EXAMPLE 7 4-[ (methylsulfonyl) methyl] coumarin EXAMPLE 8 I4-[hydroxy(methylthio)methyl]coumarin acetate4-[(methylsulfinyl)-methyl]coumarin(1 g., .0045 m.) in acetic anhydride(25 ml.) was refluxed for six hours.

' The solvent was removed under reduced pressure to give 3-hydroxy-18-[acetyl (methylthio methyl] -2-pyridineacrylic acid e-lactone Preparedby the general method as described in Example 8. Recrystallization frommethanol gave oil-white crystals (63% yield), M.P. 115-117.

Analysis.Calcd. for C H NO.,S (percent): C, 54.33; H, 4.18; N, 5.28; S,12.09. Found (percent): C, 54.49; H, 4.21; N, 5.35; S, 12.07.

EXAMPLE 3-hydroxy-[3- [acetyl (methylthio) methyl] -2-naphthaleneacrylicacid e-lactone Prepared by the general method as described in Example 8Recrystallization from DMF gave pale-yellow crystals (87% yield), M.P.201-204.

Analysis.-Calcd. for C H O S (percent): C, 64.95; H, 4.49; S, 10.20.Found (percent): C, 64.66; H, 4.57;

EXAMPLE 11 1-hydroxy-fl-[acetyl(methylthio)methyl] -2- naphthaleneacrylic acid fi-lactone Prepared by the general procedure asdescribed in Example 8. Recrystallization from DMF gave pale-yellowcrystals (85% yield), M.P. 167-169.

Analysis.Calcd. for C H O S (percent): C, 64.95; H, 4.49; S, 10.20.Found (percent): C, 64.79; H, 4.52; S, 10.19.

EXAMPLE l2.

4-[dimethoxymethyl1coumarin EXAMPLE l3 (dimethox'ymethyl) -3-hydroxy-2-pyrid ine acrylic acid E-lactone Prepared by the generalprocedure as described in Example 12. Recrystallization from ethylacetate gave white crystals (46% yield), M.P. 119-121".

Analysis.--Calcd. for C H -N0 (percent): C, 59.73; H, 5.01; N, 6.33.Found (percent): C, 59.44; H, 4.96; N, 6.42.

EXAMPLE 14 p- (Dimethoxymethyl) -1-hydroxy-2-naphthaleneacrylic acida-lactone Prepared by the" general procedure as described in Example 12.Recrystallization from ethyl acetate gave pale-yellow crystals (72%yield), M.PL 155-160.

Analysis.-Calcd. for 0 E 0, (percent): C, 71.10; H, 5.22. Found(percent): C, 70.83; H, 5.31.

6 EXAMPLE 1s 4-formylcoumarin A suspension of4-(dirnethoxymethyl)eoumarin (112 g., 0.055 m.) in 20% hydrochloric acid(20 ml.) was refluxed with stirring for three hours. The reactionmixture was cooled. The bright yellow solid was filtered off andrecrystallized from ethyl acetate to give fine yellow needles (9 g.,93%), M.P. l57.

AnalysisF-Calcd. for C H 0 (percent): C, 68.96; H, 3.47. Found(percent): C, 68.79; H, 3.54.

EXAMPLE 16 4formyl-2H-naphtha[l,2-b] pyran-Z-one Prepared by the sameprocedure as described in Example 15. Recrystallization from ethylacetate gave yellow crystals (86% yield), M.P. ZOO-203.

Analysis.--Calcd. for C I-I 0 (percent): C, 74.99; H, 3.59. Found(percent): C, 74.93; H, 3.71.

EXAMPLE 17 4-(hydroxymethyl)coumarin Sodium borohydride (0.0025 m.) wasadded to a solution of 4-formylcoumarin (1.74 g. 0.0025 111.) in aqueousdioxane at room temperature. The reaction mixture was stirred for threehours at room temperature. The dioxane was removed under reducedpressure to give a white solid. The product was washed with water, driedand recrystallized from ethyl acetate to give white needles (1.5 g.,85%), M.P. 137-1138".

Analysis.-Calcd. for C H 0 (percent): C, 68.18; H, 4.58. Found(percent): C, 68.34; H, 4.60.

EXAMPLE 18 Coumafin-4carboxylic acid 4-formylcoumarin (1.74 g., 0.01 m.)was added to a suspension of silver oxide (prepared by adding silvernitrate (2 g.) in water (25 ml.) to sodium hydroxide (l g.) in water (5ml.)). The reaction mixture was stirred at room temperature for one hourand filtered. The residue was washed with hot water. The filtrate andwashings were combined, acidified at ice-bath temperature with 10 Nhydrochloric acid and extracted with ethyl acetate. The extracts weredried over MgSO; and evaporated to give a yellow gum, which crystallizedfrom ethyl acetate. Recrystallization from ethyl acetate gave yellowcrystals (0.6 g., 32%), M.P. -182".

Analysis.Calcd. for C1QPH3O4 (percent): C, 63.16; H, 3.18. Found(percent): C, 63.31; H, 3.30.

EXAMPLE l9 4-{ (3,4-dimethylphenyl)imino]methy1}coumarin A mixture of4formylcoumarin (1.74 g., 0.01 m.) and 3,4dimethylaniline (1.2 1 g.,0.01 m.) in benzene (50 ml.) was refluxed under a water separator forthree hours. The solvent was removed under reduced pressure to give ayellow solid. Recrystallization from ethyl acetate gave yellow crystals(2.37 g., 85%), M.P. 146-148.

Analysis.Calcd. for C H NO (percent): C, 77.96; H, 5.45; N, 5.05. Found(percent): C, 77.96; H, 5.47; N, 5.14.

EXAMPLE 20 4-[ (phenylimino) methyl] coumarin Prepared by the sameprocedure as described in Example 19. Recrystallization from ethylacetate gave yellow crystals (80% yield), M.P. 148-150.

Analysis.--Calcd. for C H NO (percent): C, 77.09; H, 4.45; N, 5.62.Found (percent): C, 76.80; H, 4.53; N, 5.42.

7 EXAMPLE 21 4-formylcoumarin 4-oxime A mixture of 4-formylcoumarin(5.22 g., 0.03 m.), hydroxylamine hydrochloride (2.07 g., 0.03 m.) andsodium acetate (1 g.) in water ml.) and 95% ethanol (50 ml.) wasrefluxed for five hours. The reaction mixture was poured onto ice. Thewhite solid which precipitated was filtered off and washed with water.Recrystallization from ethyl acetate-methanol gave white crystals (4.4g., 77% M.P. 246-248".

Analysis.-Calcd. for C H NO (percent): C, 63.49; H, 3.73; N, 7.40. Found(percent): C, 63.71; H, 3.71; N, 7.17.

EXAMPLE 22 4- (3,4-dimethylanilino)methyl]coumarin Sodium borohydride(1.15 g., 0.03 m.) was added to an ice-cold suspension of4-{[(3,4-dimethylphenyl)imino] methyl}coumarin (4.0 g., 0.018 m.) inmethanol (50 ml.). The reaction mixture was stirred for three hours atroom temperature. The solvent was partially removed under reducedpressure. Water was added and the aqueous solution was extracted withether. The extracts were dried over MgSO and evaporated to give a yellowsolid. Recrystallization from ethyl acetate gave pale-yellow crystals(2.1 g., 52%), M.P. 148-149".

Analysis.-Calcd. for C H NO (percent): C, 77.40; H, 6.13; N, 5.01. Found(percent): C, 77.14; H, 6.11; N, 5.09.

We claim:

1. A compound of the formula:

wherein R is (methylsulfinyl)methyl, (methylsulfonyl) methyl,acetoxy(methylthio)methyl, dimethoxymethyl, formyl, hydroxymethyl,(oximino)methyl, (phenylimino) methyl in which the phenyl group isunsubstituted or substituted by one or two alkyl groups having 1 to 6carbon atoms, (naphthylimino)methyl, (phenylamino)methyl in which thephenyl group is unsubstituted or substituted by one or two alkyl groupshaving 1 to 6 carbon atoms or (naphthylamin0)rnethyl Z is benzene,naphthalene, phenanthrene, anthracene.

2. A compound according to claim 1 which is 4- [(methylsulfinyl) methyl]coumarin.

3. A compound according to claim 1 which the 3- hydroxy 9[(methylsulfinyl)methyl] 2 naphthaleneacrylic acid fi-lactone.

4. A compound according to claim 1 which is 1- hydroxy p[(methylsulfinyl)methyl] 2 naphthaleneacrylic acid 6-lactone.

5. A compound according to claim 1 which is 2- hydroxy p[(methylsulfonyl)methyl] 1 naphthaleneacrylic acid fi-lactone.

6. A compound according to claim 1 which is 4- [(methylsulfonyl methyl]coumarin.

7. A compound according to claim 1 which is 4- [hydroxy(methylthiomethyl] coumarin acetate.

8. A compound according to claim 1 which is 3- hydroxy fl[acetyl(methylthio)methyl]-2-naphthaleneacrylic acid fi-lactone.

9. A compound according to claim 1 which is 1- hydroxy ,3[acetyl(methylthio)methyl]-2-naphthaleneacrylic acid fi-lactone.

10. A compound according to claim 1 which is 4-(dimethoxymethyl)coumarin.

11. A compound according to claim 1 which is fi-(dimethoxyrnethyl) 1hydroxy Z-naphthaleneacrylic acid fi-lactone.

12. A compound according to claim 1 which is 4- formylcoumarin.

13. A compound according to claim 1 which is 4-formyl- ZH-naphtha 1,2-b]pyran-Z-one.

14. A compound according to claim 1 which is 4- (hydroxymethyl)coumarin.

15. A compound according to claim 1 which is 4-[(3,4-dimethylphenyl)imino]methyl coumarin.

16. A compound according to claim 1 which is 4- [(phenylimino methyl]coumarin.

17. A compound according to claim 1 which is 4-formylcoumarin 4-oxime.

18. A compound according to claim 1 which is 4-[(3,4-dimethylanilino)methyl]coumarin.

References Cited UNITED STATES PATENTS 4/1969 Giudicelli et al. 260-3432X 4/1972 Fried 260-3432 X

